PROJECT SUMMARY. Mucus dysfunction underlies the pathophysiology of a number of common respiratory diseases including asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). Asthma alone impacts 9% of the US population, resulting in considerable cost, morbidity, and occasional mortality caused by mucus hypersecretion. Recently, it was discovered that Synaptotagmin-2 (Syt2) regulates fast exocytosis of mucin granules in the lungs, and that Syt2 is limiting with respect to stimulated mucus secretion. These findings suggest that small-molecule inhibitors of Syt2 may comprise a new class of therapeutic agents allowing the clinical modulation of stimulated mucus secretion. We have developed a number of early lead inhibitors of Syt2, capable of inhibiting mucus secretion in airways of mice with IL-13-induced mucous metaplasia. These include Exo1, our early lead compound. Phase I studies will focus on the derivatization of the Exo1 compound, and success would advance a new drug class likely to improve quality-of-life for patients with a number of life threatening, chronic respiratory conditions including asthma, cystic fibrosis, and COPD. Phase II work would include formulation and delivery studies followed by pre-IND studies including GLP toxicology and animal efficacy studies in accordance with the most recent CDER guidance.